A new industry study pointed out, however, that the efficacy of this treatment in patients who are at standard risk for severe COVID-19 or who are fully vaccinated and have at least one risk factor for severe COVID-19 has not yet been established.
In the phase II–III trial published in the New England Journal of Medicine, the study team randomly assigned adults who had confirmed COVID-19 with symptom onset within the past 5 days in a 1:1 ratio to receive nirmatrelvir-ritonavir or placebo every 12 hours for 5 days.
Eligible participants were patients who were fully vaccinated against COVID-19 and who had at least one risk factor for severe disease, as well as patients without such risk factors who had never been vaccinated against SARS-CoV-2 or had not been vaccinated within the previous year. Ultimately, 1,296 patients underwent randomization and were included in the full study; approximately one-half of the participants received at least one dose of nirmatrelvir-ritonavir, while the others received a placebo.
As part of the study, participants logged the presence and severity of prespecified infectious disease signs and symptoms daily from Day 1 through Day 28. The primary end point was defined as the time to sustained alleviation of all targeted COVID-19 signs and symptoms.
The researchers also assessed COVID-19–related hospitalization and death from any cause through Day 28.
The results indicated that the median time to sustained alleviation of all targeted signs and symptoms of COVID-19 was 12 days in the nirmatrelvir-ritonavir group and 13 days in the placebo group (P = .60). The authors reported that five participants (0.8%) in the nirmatrelvir-ritonavir group and 10 (1.6%) in the placebo group were hospitalized for COVID-19 or died from any cause (difference, –0.8 percentage points; 95% CI, –2.0-0.4).
The percentages of participants with adverse events were similar in the two groups—25.8% with nirmatrelvir-ritonavir and 24.1% with placebo—with the most commonly reported treatment-related adverse events being dysgeusia (5.8%) and diarrhea (2.1%) in the nirmatrelvir-ritonavir group.
The researchers concluded that the time to sustained alleviation of all signs and symptoms of COVID-19 did not differ significantly between participants who received nirmatrelvir-ritonavir and those who received placebo.
“The ongoing clinical burden of COVID-19 necessitates the availability of effective, easily accessible oral treatments for COVID-19 that can shorten the time to resolution of symptoms and reduce the risk of severe COVID-19 leading to hospitalization or resulting in death,” the researchers wrote.
Nirmatrelvir is an orally administered antiviral agent that inhibits the SARS-CoV-2 main protease (Mpro), which is critical for viral replication. It is administered with the pharmacokinetic enhancer ritonavir to inhibit metabolism by cytochrome P450 3A4. A previous phase II-III safety and efficacy trial involving unvaccinated adults with at least one risk factor for severe COVID-19, nirmatrelvir-ritonavir was found to reduce the risk of progression to COVID-19–related hospitalization or death from any cause by 89% and 86% compared with placebo when administered within 3 days and 5 days, respectively, after symptom onset.
The current phase II-III trial, however, evaluated the efficacy and safety of nirmatrelvir-ritonavir in nonhospitalized adults with symptomatic COVID-19 who either were at standard risk for severe COVID-19 (i.e., without risk factors for severe illness, either unvaccinated or without vaccination within the previous 12 months) or were fully vaccinated and at high risk for progression to severe COVID-19.
“Results from the trial provide some intriguing observations about the use of nirmatrelvir–ritonavir in vaccinated patients who have risk factors for severe COVID-19,” according to the researchers from Pfizer Inc., and colleagues. “Among the patients who underwent randomization, COVID-19–related hospitalization or death from any cause occurred in 5 participants in the nirmatrelvir–ritonavir group and 10 in the placebo group (with the only death occurring in the placebo group). In the subgroup of high-risk participants, the numbers with this outcome were 3 and 7, respectively (difference in risk, –1.3 percentage points; 95% CI, –3.3 to 0.7). These data complement those from the Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients (EPIC-HR) trial, which enrolled unvaccinated patients with risk factors for severe COVID-19.”
The authors explained that the numbers of COVID-19–related hospitalizations and deaths from any cause in this trial are consistent with and supported by recent real-world data.
“In this trial, we assessed the safety and efficacy of nirmatrelvir–ritonavir as an antiviral agent against SARS-CoV-2 in symptomatic, nonhospitalized, vaccinated or unvaccinated adult,” the study concluded. “Nirmatrelvir–ritonavir was not associated with a significantly shorter time to sustained alleviation of COVID-19 symptoms than placebo, and the usefulness of nirmatrelvir–ritonavir in patients who are not at high risk for severe COVID-19 has not been established.”
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